This project is concerned with the mechanisms for regulating the strength of synaptic transmission. Various forms of synaptic plasticity will be studied, including facilitation, augmentation, post-tetanic potentiation, and long-term potentiation. These processes are involved in synaptic information processing, shaping of motor responses and behaviors, and adaptations of neural circuits to previous experience, and are thought to be essential for higher cognitive functions such as associative learning. Experiments will focus on answering the following specific questions: 1) How does Ca2+ cause synaptic facilitation, augmentation, and potentiation? Presynaptic Ca2+ entering during action potentials may bind to distinct sites to cause phasic exocytosis (the fast release of transmitter immediately following a spike), and other sites to facilitate, augment, and potentiate subsequent release. 2) What is the stoichiometry of Ca2+ action in exocytosis and facilitation? The first process may require high Ca2+ cooperativity, while facilitation may not. These experiments will be done at crayfish neuromuscular junctions and the squid giant synapse. 3) How does depolarization modulate transmitter release? Subthreshold depolarization at the squid giant synapse can enhance spike-evoked release without altering Ca2+ influx; this may reflect a direct Ca2+-independent modification of the exocytotic machinery, or a facilitating or potentiating effect of a rise in [Ca2+]i caused by opening Ca2+ channels. 4) Can genuine long-term potentiation be elicited solely by a rise in postsynaptic [Ca2+]i? A requirement for simultaneous afferent activity and a rise in postsynaptic [Ca2+]i to establish long-term potentiation in mammalian hippocampal CA1 pyramidal cells will be tested. 5) Is the rate- limiting step in Ca2+-evoked peptide secretion different from that for acetylcholine release at co-transmitting synapses? At bullfrog synapses onto sympathetic ganglion neurons, ACh and the peptide LHRH are co- released. Exocytosis of docked vesicles and mobilization of vesicles to release sites may be rate-liming Ca2+-dependent steps in secretion of these respective transmitters. 6) What are the parameters of Ca2+- regulation of growth cone extension? In Helisoma neurons, neurite growth may be enabled by [Ca2+]i in a particular range of intermediate concentration, and directed growth such as turning toward targets may be similarly controlled. These questions will be explored using techniques of electrophysiological recording, fluorescent measurement of [Ca2+]i, and control of [Ca2+]i using photolabile Ca2+ chelators.